INVESTIGATING THE IMPACT OF DIFFUSE AXONAL INJURY ON WORKING MEMORY PERFORMANCE FOLLOWING TRAUMATIC BRAIN INJURY USING FUNCTIONAL AND DIFFUSION NEUROIMAGING METHODS. by Gary R. Turner A thesis submitted in conformity with the requirements for the degree of Doctorate of Philosophy, Graduate Department of Psychology in the University of Toronto © Copyright by Gary R. Turner, 2008 ii Investigating the impact of diffuse axonal injury on working memory performance following traumatic brain injury using functional and diffusion neuroimaging methods. Gary R. Turner, Ph.D., 2008 Department of Psychology, University of Toronto Abstract Traumatic brain injury (TBI) is a leading cause of disability globally. Cognitive deficits represent the primary source of on-going disability in this population, yet the mechanisms of these deficits remain poorly understood. Here functional and diffusion-weighted imaging techniques were employed to characterize the mechanisms of neurofunctional change following TBI and their relationship to cognitive function. TBI subjects who had sustained moderate to severe brain injury, demonstrated good functional and neuropsychological recovery, and screened positive for diffuse axonal injury but negative for focal brain lesions were recruited for the project. TBI subjects and matched controls underwent structural, diffusion-weighted and functional MRI. The functional scanning paradigm consisted of a complex working memory task with both load and executive control manipulations. Study one demonstrated augmented functional engagement for TBI subjects relative to healthy controls associated with executive control processing but not maintenance operations within working memory. In study two, multivariate neuroimaging analyses demonstrated that activity within a network of bilateral prefrontal cortex (PFC) and posterior parietal regions was compensatory for task performance in the TBI sample. Functional connectivity analyses revealed that a common network of bilateral PFC regions was active in both groups during working memory performance, although this activity was behaviourally relevant at lower iii levels of task demand in TBI subjects relative to healthy controls. In study three, diffusion- imaging was used to characterize the impact of diffuse white matter pathology on these neurofunctional changes. Unexpectedly, decreased white matter integrity was not correlated with working memory performance following TBI. However, markers of white matter pathology did inversely correlate with the compensatory functional changes observed previously. These results implicate diffuse white matter pathology as a primary mechanism of functional brain change following TBI. Moreover, reactive neurofunctional changes appear to mediate the impact of diffuse injury following brain trauma, suggesting new avenues for neurorehabilitation in this population. iv Acknowledgements This work would not have been possible without the generous support and guidance of my supervisor, Brian Levine. His intellectual mentorship and unwavering support over the course of my doctoral studies has been invaluable. I consider our collaborations on this project merely the prelude to what I hope will be an enduring friendship and research partnership. I also thank my committee members, Morris Moscovitch and Randall McIntosh for their guidance and support throughout the project. I owe an enormous debt of gratitude as well to Robin Green, who initially set me on course for this wondrous adventure and who has become a mentor, life coach and close personal friend over these last few years. I am deeply grateful for the enormous support of the Levine lab research team who provided invaluable assistance with this project and others throughout my tenure in the lab. Specifically, for their help on this dissertation project, I offer my heartfelt thanks to Adriana Restagno and Marina Mandic. Also for their friendship and support I especially thank Charlene O’Connor as well as Nathan Spreng, Eva Svoboda, Nadine Richard, and, for always keeping me grounded, Asaf Gilboa. My family has continued to be an unending source of strength, support, encouragement and love through all of my endeavours and I owe them everything. All I have been able to accomplish over the tenure of my dissertation studies I owe first and foremost to my life partner Marcelo Martins. His support, patience and generosity has provided me with the strength to weather the hard spots and the confidence to celebrate the successes. I could not imagine this journey without him. v Table of Contents Abstract . ii Acknowledgements . .iv Table of Contents . v List of Tables . vii List of Figures . .viii General Introduction . 1 Chapter 1: Augmented neural activity during working memory following diffuse axonal injury ………. .13 Abstract . .13 Introduction . .14 Method . 15 Results . 21 Discussion . 28 Chapter 2: Compensatory neural recruitment during verbal working memory performance after TBI: evidence for an altered functional engagement hypothesis . .32 Abstract . 32 Introduction . .33 Method . 36 Results . .40 Discussion . 57 Conclusion . 63 Chapter 3: Diffuse axonal injury as a mechanism for functional brain changes following traumatic brain injury: an integrated diffusion-weighted and functional imaging study. .65 vi Abstract . .65 Introduction . .67 Method . 71 Results . .78 Discussion. .91 Conclusion . 97 General Discussion . .98 vii List of Tables Chapter 1 Table 1.1: TBI patient demographics, acute injury characteristics, structural neuroimaging data, and neuropsychological test data. .16 Table 1.2: Activation cluster maxima corresponding to maximal BOLD signal changes during the Alphabetize vs. Maintain conditions . 26 Chapter 2 Table 2.1: Cluster maxima from the behaviour PLS (ST-bPLS) analysis for the control group (See figure 2.1a). 45 Table 2.2: Cluster maxima from the behaviour PLS (ST-bPLS) analysis for the TBI group (See figure 2.1b). .46 Table 2.3: Cluster maxima from the combined behaviour and seed (ST-bPLS & ST-sPLS) analysis for the left inferior frontal gyrus seed (see figure 2.3) . 53 Table 2.4: Cluster maxima from the combined behaviour and seed (ST-bPLS & ST-sPLS) analysis for the right posterior middle frontal gyrus (BA 46 / 44) seed . 55 Chapter 3 Table 3.1: Voxel cluster coordinate and maxima for the control versus TBI whole brain FA comparison . 80 Table 3.2: Suprathreshold activation cluster maxima from LV 1 (p < .001) in the Seed and Genu PLS analysis (see Figure 3.4). ….. .86 Table 3.3: Suprathreshold activation cluster maxima from LV 1 (p < .001) in the Behaviour, Seed and Genu PLS analysis (TBI group only, see Figure 3.5). Seed was placed in right lateral middle frontal gyrus (BA 46/44). All abbreviations as in Table 3.2.. .……88 Table 3.4: Regions where white matter FA is predicted by BOLD response in right GFm during Alphabetize 5 task (TBI participants only). Letters correspond to Figure 3.6 . …. .90 viii List of Figures Chapter 1 Figure 1.1: Schematic of fMRI behavioural paradigm. ……………18 Figure 1.2: Behavioural data for Alphaspan task during fMRI scanning. …23 Figure 1.3: Areas of maximal BOLD signal change in the Executive Demand contrast . 25 Figure 1.4: Region of interest (ROI) analysis indicating mean % change difference between Alphabetize and Maintain conditions for the control group and individual TBI participants . ..28 Chapter 2 Figure 2.1.a: Brain regions demonstrating significant correlations between brain response and task accuracy in control participants. 44 Figure 2.1.b: Brain regions demonstrating significant correlations between brain response and task accuracy in TBI participants. 44 Figure 2.2: Correlations between brain activity in anterior middle frontal gyrus seed regions (highlighted in Figure 2.1). …47 Figure 2.3: Brain regions demonstrating reliable and positive correlations with left inferior frontal gyrus (BA 44/6) activity and task accuracy during Alphabetize 5 trials in the control group . 52 Figure 2.4: Brain regions demonstrating reliable and positive correlations with left inferior frontal gyrus (BA 44/6) activity and task accuracy during Alphabetize 5 trials in the control group. 54 Figure 2.5: Conceptual representation of combined behavioural and seed partial least squares analysis . … .57 Chapter 3 Figure 3.1: Group differences in voxel-wise distribution of white matter FA values . .79 Figure 3.2: Regions demonstrating significant differences in white matter FA between control and TBI participants. ..80 ix Figure 3.3: Correlations between callosal FA and Accuracy on the Alphabetize 5 letter working memory task . 82 Figure 3.4: Brain regions demonstrating reliable and positive correlations with right GFm seed (A5, F3, F5) and negative correlations with Genu FA (all tasks) in TBI subjects . …85 Figure 3.5: Brain regions demonstrating reliable and positive correlations with right GFm seed (A5, F3, F5) and negative correlations with Genu FA (all tasks) in TBI subjects. .87 Figure 3.6: Regions where activity (i.e. BOLD response) in right middle frontal gyrus during Alphabetize 5 condition predicted lower white matter FA. .. 89 INTRODUCTION Dissertation objectives and key research questions Traumatic brain injury (TBI) represents a significant and growing public health concern. World-wide incidence rates for TBI range from 180 to 500 cases per 100,000 population per year (CDC, 2001), with trauma-related brain injury poised to become the third leading cause of death and disability globally by 2020 (Povlishock & Katz, 2005). TBI survivors often